3790
A.-C. Dublanchet et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3787–3790
Synthesis of inhibitor 1 and related analogues is based
on the versatile palladium-catalyzed coupling chemistry.
Compounds 1–4 were synthesized, as shown in Scheme
1. Briefly, an oxidation and amide formation sequence
yielded the common intermediate A, which was either
directly coupled under Suzuki conditions with boronic
acids to give products 1 and 2 or transformed into a tri-
flate to yield final product 3 or eventually derivatized
into a stannane to undergo a Stille coupling to yield 4.
Compound 5 was prepared in the same manner using
4-(4-bromophenyl)-N-(2-morpholin-4-ylethyl)thiophene-
2-carboxamide intermediate that was obtained through
a Sandmeyer sequence. Compounds 6, 7, and 10 were
prepared from a common intermediate C, derived from
the starting aldehyde following a Suzuki sequence,
through amide bond formation with readily available
amines as shown in Scheme 2. Eventually, preparation
of compound 11 is achieved following the chemical
route shown in Scheme 3.
Scheme 3. Preparation of compound 11. Reagents and conditions:
(a) pyridylboronic acid, Pd(PPh3)4, K3PO4 aq 2 M, DME, 80 °C;
(b) MeOH, HCl, 65 °C; (c) lithium hydroxide, EtOH/H2O; (d) (2R)-
amino(phenyl) propanoate, HATU, DIEA, DMF, rt; (e) lithium
hydroxide, EtOH/H2O and then HCl 2 M.
act with the zinc active-site atom and nevertheless dis-
play affinities for MMP-12 in the nanomolar range.
X-ray crystallography data have confirmed the unique
binding mode predicted from docking experiments. Is-
sued from an activity-based and property-based optimi-
zation program, compounds such as compound 11 may
be regarded as novel, non-peptidic, low molecular
weight, non-zinc binding leads for continued develop-
ment of MMP inhibitors as drugs. On the basis of our
crystal structure and molecular modeling model, this
compound could be viewed as the starting point for
selectivity optimization over MMP-13 and physico-
chemical profile enhancement.
In summary, we have discovered a series of potent
MMP-12 inhibitors incorporating a thiophene template,
an unusual central linker compared to established MMP
binding groups. Structure-based drug design methods
led to compounds with an improved potency for
MMP-12, achieving a 1000-fold enhancement compared
to the initial hit. In contrast to the well-established
MMP inhibitors, the compounds described do not inter-
Acknowledgments
We thank Dr. Ajith Manage (Evotec-OAI) for the prep-
aration of synthetic intermediates in large scale; I. Me-
nier, N. Philippon, and M. Millet for solubility
measurements; and Dr. Annah Mancy and Anne Mou-
´
stie for determining metabolic stability values.
References and notes
Scheme 1. Preparation of compounds 1–4. Reagents and conditions:
(a) AgNO3, EtOH/NaOH aq, 40 °C; (b) (COCl)2, CH2Cl2, DMF cat.,
0 °C then rt; (c) 4-(2-aminoethyl)morpholine, Et3N, CH2Cl2, rt; (d)
R1boronic acid, Pd(PPh3)4, K3PO4 aq 2 M, DME, 80 °C; (f) i—
4-hydroxyphenylboronic acid, Suzuki cond.; ii—trifluoromethanesulf-
onic anhydride, CH2Cl2, pyridine, rt; iii—pyridine-4-boronic acid,
Suzuki cond.; (g) i—hexamethylditin, Pd(PPh3)4, DME, 80 °C; ii—
1-bromo-4-cyclohexylbenzene, LiCl, CuBr2, Pd(PPh3)4, dioxane, 80 °C.
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Scheme 2. Preparation of compounds 6, 7, and 10. Reagents and
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